The human intestine is colonized by a large and diverse population of commensal bacteria and, on occasion, is exposed to potentially pathogenic bacteria. One particular subset of intestinal bacteria have flagella, which are whip-like organelles that attach to a rotatory motor embedded in the bacterial cell wall. Flagella provide bacteria with motility and enable these microbes to reach, adhere and eventually invade or colonize a particular niche in their host. An individual flagellum is composed of approximately 20,000 subunits of the monomeric protein flagellin. Due to physical constraints by its function, flagellin has a relatively conserved structure among widely diverse bacterial species (Steiner, T. S. Infect Immun. 2007 February; 75(2):545-52).
Flagellin is highly antigenic and is a major immunoglobulin target in a variety of infectious events (Sitaraman et al., Am J Physiol Gastrointest Liver Physiol. 2005 February; 288(2):G403-6). As such, it is a potent and direct activator of the innate immune system. From the perspective of the host, flagellin is a microbial-associated molecular pattern (MAMP) i.e., a microbial-associated determinant that can be perceived by the innate immune system, typically by pattern recognition receptors. Flagellin therefore serves as a danger signal across a wide variety of eukaryotes and is a potent inducer of inflammatory effector responses in the mammalian gut (Neish, A. S., Am J Physiol Gastrointest Liver Physiol. 2007 February; 292(2):G462-6). Specifically, upon detection of miniscule levels of the monomeric protein flagellin, the mammalian germline encoded cell surface receptor Toll-like receptor 5 (TRL5) can directly promote a mucosal inflammatory response and trigger a massive induction of host gene expression designed to arm and protect the host against the invading microbe. The resulting inflammatory cascade triggered by flagellin can be profound, causing clinical manifestations and tissue damage (Gewirtz, A. T., Am J Physiol Gastrointest Liver Physiol. 2007 March; 292(3):G706-10).
Inflammatory bowel disease (IBD) is characterized by inflammation of the bowel, i.e., the large or small intestine, and causes abdominal pain, rectal bleeding and/or diarrhea. The most common types of IBD are Ulcerative Colitis and Crohn's Disease. While the inflammation in Ulcerative Colitis is more superficial and limited to the inner lining of the colon and rectum, the inflammation associate with Crohn's Disease extends from the mucosa through the entire thickness of the bowel wall and can affect any area of the gastrointestinal tract from the mouth to the anus.
IBD, in general, and Crohn's Disease, in particular, is thought to be driven by exaggerated mucosal immune responses to enteric microflora. For example, in a spontaneously colitic mouse model (C3H/HejBir mice), sera screened for differential expression of bacterial protein antigens identified hundreds of antigens, with approximately 25% being bacterial flagellins (Lodes, et al., J Clin Invest. 2004 May; 113(9):1296-306). Additionally, it has been demonstrated that flagellin released by commensal E. coli isolates activates the expression of chemokines (e.g., IL-8) that ultimately cause recruitment of activated neutrophils. Neutrophils however, are not merely an indicator of active IBD, but instead are thought to cause much of the damage and symptoms associated with active inflammation and to actually drive acute flares of IBD (Gewirtz, A. T., Am J Physiol Gastrointest Liver Physiol. 2007 March; 292(3):G706-10).
Further, the identification of a dominant-negative TLR5 polymorphism, which reduces the adaptive immune response to flagellin and negatively associates with Crohn's Disease, suggests that immune responses to flagellin are not merely associated with Crohn's Disease, but instead actually promote the pathogenic response (Gewirtz, et al., Am J Physiol Gastrointest Liver Physiol. 2006 June; 290(6):G1157-63). Notwithstanding, the specific organisms that drive the immune response associated with IBD are not well defined and there still remains a question as to whether host responses to flagellin are, in fact, part of the healthy, beneficial immune response or, alternatively, whether they are part of an aberrant immune response that should be therapeutically targeted (Gewirtz, A. T., Am J Physiol Gastrointest Liver Physiol. 2007 March; 292(3):G706-10).
Current treatments for IBD typically involve administration of anti-inflammatory drugs, corticosteroids such as prednisone, immune system suppressors, antibiotics, as well as anti-diarrheals, laxatives, pain relievers or other over-the-counter (OTC) drugs, and in some cases surgery. These therapies, however, have clear drawbacks in that they are associated with potentially long-term side effects and are merely palliative in nature. Accordingly, improved treatments for IBD, as well as other flagellated bacterial infections would be beneficial.